T1013 A Multicentric, Double-Blind, Randomized Placebo-Controlled Trial of High Dose Ursodeoxycholic Acid in Patients with Non-Alcoholic Steatohepatitis (NASH)

Aims: To date, there is no proven effective therapy for NASH.Hepatoprotectants directly targeting liver inflammation and/or fibrosis could be a useful treatment approach.We evaluated the efficacy and safety of high dose ursodeoxycholic acid (HD-UDCA) in patients with NASH in a double-blind RCT.Methods: Patients with histologically proven NASH and ALT > 50 IU/L recruited in 18 centers were randomized to receive HD-UDCA (30 mg/kg/day) or placebo for 12 months.The primary efficacy endpoint was the change from baseline at 12 months in serum ALT.All biochemical measurements were centralized.Results: A total of 126 patients (64 placebo and 62 HD-UDCA) were enrolled (intent-to-treat population).There were 75% males, mean (± SD) age was 49.7 (±11.5)years, and BMI 30.9(±5.1)kg/m 2 .Metabolic syndrome, hypertension, and type-2 diabetes were present in 40%, 32%, and 35% of patients respectively.After 12 months, ALT decreased by (mean ± SD) -28±55% under HD-UDCA compared to -2±35% under placebo (p < 0.001).ALT levels normalized ( 35 IU/L) in 25% and 5% of patients on HD-UDCA and placebo, respectively (p = 0.003).Mean (± SD) decreases in serum AST and GGT levels were -8±59% and -51±28% respectively on HD-UDCA compared to placebo where they increased by +9±37% (p < 0.001) and +19±48% (p < 0.001) respectively.All results were confirmed in the per protocol population.Asthenia and right upper quadrant pain (RUQP) were reported more frequently at baseline in the HD-UDCA group than in the placebo group; this difference disappeared early during treatment (3 months).Changes in serum markers of insulin resistance, fibrosis, inflammation and apoptosis will be reported.The HD-UDCA group experienced more mild diarrhea, abdominal pain, and gastrointestinal motility disorders than the placebo group.Conclusions: This RCT demonstrated a significant and marked biochemical response to HD-UDCA in NASH patients and suggested symptomatic improvement of asthenia and RUQP, without any significant safety concerns.This is the largest RCT to support the biochemical efficacy of HD-UDCA in NASH and provides the rationale for further studies with histological endpoints.